Tags

Type your tag names separated by a space and hit enter

Modulation of ROS/MAPK signaling pathways by okadaic acid leads to cell death via, mitochondrial mediated caspase-dependent mechanism.
Apoptosis. 2011 Feb; 16(2):145-61.A

Abstract

Okadaic acid (OA) is a specific and potent protein phosphatase inhibitor and tumor promoter. The present study establishes the role of reactive oxygen species (ROS) and mitogen activated protein kinases in cell death induced by okadaic acid. The study showed that okadaic acid is cytotoxic at 10 nM with an IC50 of 100 nM in U-937 cells. The CVDE assay and mitochondrial dehydrogenase assay showed a time dependent cytotoxicity. The phase contrast visualization of the OA treated cells showed the apoptotic morphology and was confirmed with esterase staining for plasma membrane integrity. OA activated caspases-7, 9 and 3, PARP cleavage and induced nuclear damage in a time and dose dependent manner. Compromised mitochondrial membrane potential, release of cytochrome-c and apoptosis inducing factor confirms the involvement of mitochondria. A time dependent decrease in glutathione levels and a dose dependent increase in ROS with maximum at 30 min were observed. ROS scavenger-N-acetyl cysteine, mitochondrial stabilizer-cyclosporin-A, and broad spectrum caspase inhibitor Z-VAD-FMK inhibited the OA induced caspase-3 activation, DNA damage and cell death but caspase-8 inhibitor had no effect. OA activated p38 MAPK and JNK in a time dependent manner, but not ERK½. MAP kinase inhibitors SB203580, SP600125 and PD98059 confirm the role of p38 MAPK and JNK in OA induced caspase-3 activation and cell death. Over all, our results indicate that OA induces cell death by generation of ROS, and activation of p38 MAPK and JNK, and executed through mitochondrial mediated caspase pathway.

Authors+Show Affiliations

Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21082355

Citation

Ravindran, Jayaraj, et al. "Modulation of ROS/MAPK Signaling Pathways By Okadaic Acid Leads to Cell Death Via, Mitochondrial Mediated Caspase-dependent Mechanism." Apoptosis : an International Journal On Programmed Cell Death, vol. 16, no. 2, 2011, pp. 145-61.
Ravindran J, Gupta N, Agrawal M, et al. Modulation of ROS/MAPK signaling pathways by okadaic acid leads to cell death via, mitochondrial mediated caspase-dependent mechanism. Apoptosis. 2011;16(2):145-61.
Ravindran, J., Gupta, N., Agrawal, M., Bala Bhaskar, A. S., & Lakshmana Rao, P. V. (2011). Modulation of ROS/MAPK signaling pathways by okadaic acid leads to cell death via, mitochondrial mediated caspase-dependent mechanism. Apoptosis : an International Journal On Programmed Cell Death, 16(2), 145-61. https://doi.org/10.1007/s10495-010-0554-0
Ravindran J, et al. Modulation of ROS/MAPK Signaling Pathways By Okadaic Acid Leads to Cell Death Via, Mitochondrial Mediated Caspase-dependent Mechanism. Apoptosis. 2011;16(2):145-61. PubMed PMID: 21082355.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of ROS/MAPK signaling pathways by okadaic acid leads to cell death via, mitochondrial mediated caspase-dependent mechanism. AU - Ravindran,Jayaraj, AU - Gupta,Nimesh, AU - Agrawal,Mona, AU - Bala Bhaskar,A S, AU - Lakshmana Rao,P V, PY - 2010/11/18/entrez PY - 2010/11/18/pubmed PY - 2011/8/24/medline SP - 145 EP - 61 JF - Apoptosis : an international journal on programmed cell death JO - Apoptosis VL - 16 IS - 2 N2 - Okadaic acid (OA) is a specific and potent protein phosphatase inhibitor and tumor promoter. The present study establishes the role of reactive oxygen species (ROS) and mitogen activated protein kinases in cell death induced by okadaic acid. The study showed that okadaic acid is cytotoxic at 10 nM with an IC50 of 100 nM in U-937 cells. The CVDE assay and mitochondrial dehydrogenase assay showed a time dependent cytotoxicity. The phase contrast visualization of the OA treated cells showed the apoptotic morphology and was confirmed with esterase staining for plasma membrane integrity. OA activated caspases-7, 9 and 3, PARP cleavage and induced nuclear damage in a time and dose dependent manner. Compromised mitochondrial membrane potential, release of cytochrome-c and apoptosis inducing factor confirms the involvement of mitochondria. A time dependent decrease in glutathione levels and a dose dependent increase in ROS with maximum at 30 min were observed. ROS scavenger-N-acetyl cysteine, mitochondrial stabilizer-cyclosporin-A, and broad spectrum caspase inhibitor Z-VAD-FMK inhibited the OA induced caspase-3 activation, DNA damage and cell death but caspase-8 inhibitor had no effect. OA activated p38 MAPK and JNK in a time dependent manner, but not ERK½. MAP kinase inhibitors SB203580, SP600125 and PD98059 confirm the role of p38 MAPK and JNK in OA induced caspase-3 activation and cell death. Over all, our results indicate that OA induces cell death by generation of ROS, and activation of p38 MAPK and JNK, and executed through mitochondrial mediated caspase pathway. SN - 1573-675X UR - https://www.unboundmedicine.com/medline/citation/21082355/Modulation_of_ROS/MAPK_signaling_pathways_by_okadaic_acid_leads_to_cell_death_via_mitochondrial_mediated_caspase_dependent_mechanism_ L2 - https://doi.org/10.1007/s10495-010-0554-0 DB - PRIME DP - Unbound Medicine ER -